rs141614470

chr1-19240364-G-Achr1-19240364-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015047.3(EMC1):c.719C>T(p.Pro240Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,164 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P240Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: EMC1 NM_015047.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.04

Genes affected

EMC1 (HGNC:28957): (ER membrane protein complex subunit 1) This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2012]

EMC1-AS1 (HGNC:54050): (EMC1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005671948).
• BP6: Variant 1-19240364-G-A is Benign according to our data. Variant chr1-19240364-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 446000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-19240364-G-A is described in Lovd as [Benign]. Variant chr1-19240364-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00425 (647/152284) while in subpopulation AFR AF= 0.0133 (551/41550). AF 95% confidence interval is 0.0123. There are 1 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMC1	NM_015047.3	c.719C>T	p.Pro240Leu	missense_variant	7/23	ENST00000477853.6
EMC1-AS1	NR_135114.1	n.282G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMC1	ENST00000477853.6	c.719C>T	p.Pro240Leu	missense_variant	7/23	1	NM_015047.3	P4
EMC1-AS1	ENST00000437898.3	n.320G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 644 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00207 AC: 520 AN: 251430 Hom.: 6 AF XY: 0.00160 AC XY: 218 AN XY: 135898

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000827

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00101 AC: 1476 AN: 1461880 Hom.: 7 Cov.: 31 AF XY: 0.000952 AC XY: 692 AN XY: 727244

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000577

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00425 AC: 647 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74476

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.00527

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0049	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.063
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0057	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.88	N;N;N
REVEL	Benign	0.029
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.53	P;P;P
Vest4		0.21
MVP		0.37
MPC		0.33
ClinPred		0.011	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141614470; hg19: chr1-19566858; COSMIC: COSV61886971; COSMIC: COSV61886971;